Dataset Information

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

ABSTRACT: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for ?-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.We observed a significant association of total zinc intake with lower fasting glucose levels (?-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (?-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

SUBMITTER: Kanoni S

PROVIDER: S-EPMC3161318 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

Kanoni Stavroula S Nettleton Jennifer A JA Hivert Marie-France MF Ye Zheng Z van Rooij Frank J A FJ Shungin Dmitry D Sonestedt Emily E Ngwa Julius S JS Wojczynski Mary K MK Lemaitre Rozenn N RN Gustafsson Stefan S Anderson Jennifer S JS Tanaka Toshiko T Hindy George G Saylor Georgia G Renstrom Frida F Bennett Amanda J AJ van Duijn Cornelia M CM Florez Jose C JC Fox Caroline S CS Hofman Albert A Hoogeveen Ron C RC Houston Denise K DK Hu Frank B FB Jacques Paul F PF Johansson Ingegerd I Lind Lars L Liu Yongmei Y McKeown Nicola N Ordovas Jose J Pankow James S JS Sijbrands Eric J G EJ Syvänen Ann-Christine AC Uitterlinden André G AG Yannakoulia Mary M Zillikens M Carola MC Wareham Nick J NJ Prokopenko Inga I Bandinelli Stefania S Forouhi Nita G NG Cupples L Adrienne LA Loos Ruth J RJ Hallmans Goran G Dupuis Josée J Langenberg Claudia C Ferrucci Luigi L Kritchevsky Stephen B SB McCarthy Mark I MI Ingelsson Erik E Borecki Ingrid B IB Witteman Jacqueline C M JC Orho-Melander Marju M Siscovick David S DS Meigs James B JB Franks Paul W PW Dedoussis George V GV

Diabetes 20110801 9

<h4>Objective</h4>Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.<h4>Research design and methods</h4>We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemi ...[more]

PMID: 21810599

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Project description:BackgroundWe examined the effects of the R325W mutation on the three-dimensional (3D) structure of the beta-cell-specific Zn2+ (zinc) transporter ZnT-8.MethodsA model of the C-terminal domain of the human ZnT-8 protein was generated by homology modeling based on the known crystal structure of the Escherichia coli (E. coli) zinc transporter YiiP at 3.8 A resolution.ResultsThe homodimer ZnT-8 protein structure exists as a Y-shaped architecture with Arg325 located at the ultimate bottom of this motif at approximately 13.5 A from the transmembrane domain juncture. The C-terminal domain sequences of the human ZnT-8 protein and the E. coli zinc transporter YiiP share 12.3% identical and 39.5% homologous residues resulting in an overall homology of 51.8%. Validation statistics of the homology model showed a reasonable quality of the model. The C-terminal domain exhibited an alphabetabetaalphabeta fold with Arg325 as the penultimate N-terminal residue of the alpha2-helix. The side chains of both Arg325 and Trp325 point away from the interface with the other monomer, whereas the epsilon-NH3+ group of Arg325 is predicted to form an ionic interaction with the beta-COO- group of Asp326 as well as Asp295. An amino acid alignment of the beta2-alpha2 C-terminal loop domain revealed a variety of neutral amino acids at position 325 of different ZnT-8 proteins.ConclusionsOur validated homology models predict that both Arg325 and Trp325, amino acids with a helix-forming behavior, and penultimate N-terminal residues in the alpha2-helix of the C-terminal domain, are shielded by the planar surface of the three cytoplasmic beta-strands and hence unable to affect the sensing capacity of the C-terminal domain. Moreover, the amino acid residue at position 325 is too far removed from the docking and transporter parts of ZnT-8 to affect their local protein conformations. These data indicate that the inherited R325W abnormality in SLC30A8 may be tolerated and results in adequate zinc transfer to the correct sites in the pancreatic islet cells and are consistent with the observation that the SLC30A8 gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.

Project description:The human zinc transporter ZnT8 (SLC30A8) is expressed primarily in pancreatic β-cells and plays a key function in maintaining the concentration of blood glucose through its role in insulin storage, maturation and secretion. ZnT8 is an autoantigen for Type 1 diabetes (T1D) and is associated with Type 2 diabetes (T2D) through its risk allele that encodes a major non-synonymous single nucleotide polymorphism (SNP) at Arg325. Loss of function mutations improve insulin secretion and are protective against diabetes. Despite its role in diabetes and concomitant potential as a drug target, little is known about the structure or mechanism of ZnT8. To this end, we expressed ZnT8 in Pichia pastoris yeast and Sf9 insect cells. Guided by a rational screen of 96 detergents, we developed a method to solubilize and purify recombinant ZnT8. An in vivo transport assay in Pichia and a liposome-based uptake assay for insect-cell derived ZnT8 showed that the protein is functionally active in both systems. No significant difference in activity was observed between full-length ZnT8 (ZnT8A) and the amino-terminally truncated ZnT8B isoform. A fluorescence-based in vitro transport assay using proteoliposomes indicated that human ZnT8 functions as a Zn2+/H+ antiporter. We also purified E. coli-expressed amino- and carboxy-terminal cytoplasmic domains of ZnT8A. Circular dichroism spectrometry suggested that the amino-terminal domain contains predominantly α-helical structure, and indicated that the carboxy-terminal domain has a mixed α/β structure. Negative-stain electron microscopy and single-particle image analysis yielded a density map of ZnT8B at 20 Å resolution, which revealed that ZnT8 forms a dimer in detergent micelles. Two prominent lobes are ascribed to the transmembrane domains, and the molecular envelope recapitulates that of the bacterial zinc transporter YiiP. These results provide a foundation for higher resolution structural studies and screening experiments to identify compounds that modulate ZnT8 activity.

Dataset Information

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

Publications

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

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